Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serum levels of HDL are inversely correlated with the risk of coronary heart disease. The anti-atherogenic effect of HDL is partially mediated by its major protein constituent apoA-I. In this study, we identify bile acids that are activators of the nuclear receptor farnesoid X receptor (FXR) as negative regulators of human apoA-I expression. Intrahepatocellular accumulation of bile acids, as seen in patients with progressive familial intrahepatic cholestasis and biliary atresia, was associated with diminished apoA-I serum levels. In human apoA-I transgenic mice, treatment with the FXR agonist taurocholic acid strongly decreased serum concentrations and liver mRNA levels of human apoA-I, which was associated with reduced serum HDL levels. Incubation of human primary hepatocytes and hepatoblastoma HepG2 cells with bile acids resulted in a dose-dependent downregulation of apoA-I expression. Promoter mutation analysis and gel-shift experiments in HepG2 cells demonstrated that bile acid-activated FXR decreases human apoA-I promoter activity by a negative FXR response element mapped to the C site. FXR bound this site and repressed transcription in a manner independent of retinoid X receptor. The nonsteroidal synthetic FXR agonist GW4064 likewise decreased apoA-I mRNA levels and promoter activity in HepG2 cells.
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PMID:Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element. 1192 23

Bile acids are required for the absorption of lipids and fat-soluble vitamins. The hepatic biosynthesis of bile acids is a major pathway for the catabolism and removal of cholesterol from the body. Because of their intrinsic toxicity, bile acid synthesis, transport, and metabolism must be tightly regulated. It is now apparent that members of the nuclear receptor family of lipid-activated transcription factors are key regulators of these physiological processes. A greater understanding of these receptors should afford novel opportunities for therapeutic intervention in chronic diseases such as cholestasis and dyslipidemia.
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PMID:Nuclear receptors. I. Nuclear receptors and bile acid homeostasis. 1201 16

Bile salt export pump (BSEP) is a major bile acid transporter in the liver. Mutations in BSEP result in progressive intrahepatic cholestasis, a severe liver disease that impairs bile flow and causes irreversible liver damage. BSEP is a target for inhibition and down-regulation by drugs and abnormal bile salt metabolites, and such inhibition and down-regulation may result in bile acid retention and intrahepatic cholestasis. In this study, we quantitatively analyzed the regulation of BSEP expression by FXR ligands in primary human hepatocytes and HepG2 cells. We demonstrate that BSEP expression is dramatically regulated by ligands of the nuclear receptor farnesoid X receptor (FXR). Both the endogenous FXR agonist chenodeoxycholate (CDCA) and synthetic FXR ligand GW4064 effectively increased BSEP mRNA in both cell types. This up-regulation was readily detectable at as early as 3 h, and the ligand potency for BSEP regulation correlates with the intrinsic activity on FXR. These results suggest BSEP as a direct target of FXR and support the recent report that the BSEP promoter is transactivated by FXR. In contrast to CDCA and GW4064, lithocholate (LCA), a hydrophobic bile acid and a potent inducer of cholestasis, strongly decreased BSEP expression. Previous studies did not identify LCA as an FXR antagonist ligand in cells, but we show here that LCA is an FXR antagonist with partial agonist activity in cells. In an in vitro co-activator association assay, LCA decreased CDCA- and GW4064-induced FXR activation with an IC(50) of 1 microm. In HepG2 cells, LCA also effectively antagonized GW4064-enhanced FXR transactivation. These data suggest that the toxic and cholestatic effect of LCA in animals may result from its down-regulation of BSEP through FXR. Taken together, these observations indicate that FXR plays an important role in BSEP gene expression and that FXR ligands may be potential therapeutic drugs for intrahepatic cholestasis.
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PMID:Lithocholic acid decreases expression of bile salt export pump through farnesoid X receptor antagonist activity. 1205 24

The nuclear receptor FXR is the sensor of physiological levels of enterohepatic bile acids, the end products of cholesterol catabolism. Here we report crystal structures of the FXR ligand binding domain in complex with coactivator peptide and two different bile acids. An unusual A/B ring juncture, a feature associated with bile acids and no other steroids, provides ligand discrimination and triggers a pi-cation switch that activates FXR. Helix 12, the activation function 2 of the receptor, adopts the agonist conformation and stabilizes coactivator peptide binding. FXR is able to interact simultaneously with two coactivator motifs, providing a mechanism for enhanced binding of coactivators through intermolecular contacts between their LXXLL sequences. These FXR complexes provide direct insights into the design of therapeutic bile acids for treatment of hyperlipidemia and cholestasis.
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PMID:Structural basis for bile acid binding and activation of the nuclear receptor FXR. 1271 93

The ABC transporter, Mrp4, transports the sulfated steroid DHEA-s, and sulfated bile acids interact with Mrp4 with high affinity. Hepatic Mrp4 levels are low, but increase under cholestatic conditions. We therefore inferred that up-regulation of Mrp4 during cholestasis is a compensatory mechanism to protect the liver from accumulation of hydrophobic bile acids. We determined that the nuclear receptor CAR is required to coordinately up-regulate hepatic expression of Mrp4 and an enzyme known to sulfate hydroxy-bile acids and steroids, Sult2a1. CAR activators increased Mrp4 and Sult2a1 expression in primary human hepatocytes and HepG2, a human liver cell line. Sult2a1 was down-regulated in Mrp4-null mice, further indicating an inter-relation between Mrp4 and Sult2a1 gene expression. Based on the hydrophilic nature of sulfated bile acids and the Mrp4 capability to transport sulfated steroids, our findings suggest that Mrp4 and Sult2a1 participate in an integrated pathway mediating elimination of sulfated steroid and bile acid metabolites from the liver.
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PMID:Interactions between hepatic Mrp4 and Sult2a as revealed by the constitutive androstane receptor and Mrp4 knockout mice. 1500 17

Biliary function is a vital function of the liver which results from the vectorial transport of endogenous and exogenous substrates through three compartments sequentially: the vascular space, the cellular space and the biliary space. The biliary function is responsible for the homeostasis of lipid metabolism in particular of cholesterol metabolism, the elimination of toxic endo--and xenobiotics such as (bilirubin, lipid bacteria products (endotoxin)) and several inflammatory mediators. Bile elaborated in canaliculi, is modified by cholangiocytes through secretion and absorption. Bile is essential for the intestinal digestion and absorption of nutriments. The main determinant of bile formation is an osmotic filtration process resulting from active transport of bile acids and other osmotic solutes (glutathione). Most of the membrane transporters ensuring bile formation have now been identified. The expression of these membrane transporters is regulated through transcriptional and post-tranductional mechanisms. Transcriptional regulation is under the control of nuclear receptors activated by ligands such as bile acids, which act as endogenous steroids synthesized from cholesterol in hepatocytes. Cholestatic liver diseases comprise genetic diseases resulting from the complex interaction between genetic and environmental factors. Monogenic cholestatic diseases recently identified illustrate the key role of membrane transporters in biliary function. Bile acids and inflammatory mediators are potent modulators transporters and nuclear receptor genes and thus trigger an adaptative response to cholestasis. The extent of this adaptative response could explain the compelling phenotypic variability of cholestatic diseases in childhood and adults. The firstline medical treatment is currently ursodeoxycholic acid and in case of failure of this medical treatment, liver transplantation is required. Recent progress in the molecular pathogenesis of bile formation and cholestatic liver diseases is expected to provide the design of drugs targeted to the molecular abnormalities typical of cholestatic diseases.
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PMID:[Molecular mechanisms of bile formation and cholestatic diseases]. 1514 3

Bile acids are end products of cholesterol metabolism. They are exclusively synthesised by the liver and subsequently secreted via the bile duct into the intestine to facilitate the absorption of dietary fat and fat-soluble vitamins. Nuclear receptors are ligand-activated transcription factors. The farnesoid X receptor (FXR) has recently been identified as a bile acid-activated nuclear receptor. FXR controls bile-acid synthesis, conjugation and transport, as well as lipid metabolism. Recent advances in FXR biology demonstrate that FXR may represent a valuable target for the identification of novel drugs to treat dyslipidaemia and cholestasis. However, for therapeutic purposes the development of selective FXR modulators, which only activate or inhibit specific FXR target genes and as such induce specific responses, will be required.
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PMID:The farnesoid X receptor: a novel drug target? 1533 Jul 45

Sterol 12alpha-hydroxylase (CYP8B1) catalyzes cholic acid synthesis in the liver and is feedback inhibited by bile acids. In addition to activating farnesoid X receptor (nuclear receptor subfamily 1H4), bile acids also induce inflammatory cytokines in hepatocytes. The objective of this study was to investigate the mechanism by which inflammatory cytokines inhibit human CYP8B1 gene transcription. Real-time PCR assays revealed that both chenodeoxycholic acid (CDCA) and interleukin-1beta (IL-1beta) markedly reduced CYP8B1, cholesterol 7alpha-hydroxylase CYP7A1 and hepatic nuclear factor 4alpha (HNF4alpha) mRNA expression levels in human primary hepatocytes. However, CDCA induced, but IL-1beta reduced, small heterodimer partner (SHP) mRNA expression. IL-1beta inhibited human CYP8B1 reporter activity only in liver cells, and a c-Jun NH(2)-terminal kinase (JNK)-specific inhibitor-blocked IL-1beta inhibition. Activated JNK1 or c-Jun inhibited, whereas their dominant negative forms blocked, IL-1beta inhibition of CYP8B1 transcription. Mutagenesis analyses mapped an IL-1beta response element to a previously identified bile acid response element, which contains an HNF4alpha binding site. A dominant negative HNF4alpha inhibited CYP8B1 gene transcription and ectopically expressed HNF4alpha blocked IL-1beta inhibition. Furthermore, IL-1beta inhibited HNF4alpha gene transcription, protein expression, and binding to the CYP8B1 gene. JNK1 phosphorylated HNF4alpha and a JNK-specific inhibitor blocked the IL-1beta inhibition of HNF4alpha expression. These results suggest that IL-1beta inhibits CYP8B1 gene transcription via a mitogen-activated protein kinase/JNK pathway that inhibits HNF4alpha gene expression and its DNA-binding ability. This mechanism may play an important role in the adaptive response to inflammatory cytokines and in the protection of the liver during cholestasis.
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PMID:Cytokine regulation of human sterol 12alpha-hydroxylase (CYP8B1) gene. 1555 May 63

Proinflammatory cytokines such as TNF-alpha and IL-1beta lead to downregulation of hepatic organic anion transporters in cholestasis. This adapted response is transcriptionally mediated by nuclear hormone receptors and liver-specific transcription factors. Because little is known in vivo about cytokine-dependent regulatory events, mice were treated with either TNF-alpha or IL-1beta for up to 16 h. Transporter mRNA expression was determined by Northern blot analysis, nuclear activity, and protein-expression of transactivators by EMSA and Western blotting. TNF-alpha induces a sustained decrease in Ntcp, Oatp1/Oatp1a1, and Bsep mRNA expression but exerts only transient [multidrug resistance-associated protein 2 (Mrp2)] or no effects (Mrp3) on Mrps. In addition to Ntcp and Oatp1/Oatp1a1, IL-1beta also downregulates Bsep, Mrp2, and Mrp3 mRNAs to some extent. To study transcriptional regulation, Ntcp and Bsep promoters were first cloned from mice revealing a new distal Ntcp hepatocyte nuclear factor 1 (HNF-1) element but otherwise show a conserved localization to known rat regulatory elements. Changes in transporter-expression are preceeded by a reduction in binding activities at IR-1, ER-8, DR-5, and HNF-1alpha sites after 4 h by either cytokine, which remained more sustained by TNF-alpha in the case of nuclear receptors. Nuclear protein levels of retinoid X receptor (RXR)-alpha are significantly decreased by TNF-alpha but only transiently affected by IL-1beta. Minor reductions of retinoic acid receptor, farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor nuclear proteins are restricted to 4 h after cytokine application and paralleled by a decrease in mRNA levels. Basolateral and canalicular transporter systems are downregulated by both cytokines, TNF-alpha and IL-1beta. Activity of HNF-1alpha as regulator of mNtcp is suppressed by both cytokines. Decreased binding activities of nuclear receptor heterodimers may be explained by a reduction of the ubiquitous heterodimerization partner RXR-alpha.
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PMID:Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver. 1586 Jun 42

Recent studies reveal that bile acids are signalling molecules that activate several nuclear receptors and regulate many physiological pathways and processes to maintain bile acid and cholesterol homeostasis. Analysis of orphan receptor expression patterns in enterohepatic tissues identified bile acids as ligands for farnesoid X receptor (FXR). The primary bile acid chenodeoxycholic acid (CDCA) was shown to be the most potent FXR ligand in vitro at an EC50 of 10-50 microM. FXR can also be activated by the secondary bile acids lithocholic acid (LCA) and deoxycholic acid (DCA). Upon activation FXR heterodimerises with 9-cis retinoic X receptor (RXR) and regulates a cohort of genes involved in cholesterol catabolism and bile acids biosynthesis. Thus bile acid-activated FXR directly induces expression of Small Heterodimer Partner (SHP), a nuclear receptor that suppresses bile acid biosynthesis down-regulates the Na+ taurocholate cotransport peptide (NTCP), a pump depicted to transport bile acids from the lumen into hepatocyte, and induces expression of bile salt export pump (BSEP), the principal bile acid efflux transporter in the liver. As demonstrated by the Fxr null mice, FXR defends the liver against cholestasis. The 6-ethyl derivative of CDCA (6-ECDCA) is approximately 100 fold more potent than CDCA in activating FXR in vitro. In vivo administration of 6-ECDCA protects against cholestasis induced by estrogen and LCA in rats providing evidence that development of potent FXR agonists might represent a new approach for the treatment of cholestastic disorders.
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PMID:Role of FXR in regulating bile acid homeostasis and relevance for human diseases. 1617 89


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